Vitamin intermediates and their preparation



Patented Sept. 19, 1944 UNITED STATES PATENT OFFICE VITAMININTERMEDIATES' AND THEIR PREPARATION No Drawing.

Original application January 4,

1941, Serial No. 373,193. Divided and this D- plication August 16, 1843,Serial No. 498,872

8Claims.

The invention relates to the preparation of a,-dihydroxy-fi,p-dimethylbutyramide compounds, and this application is adivision of our copending application, Serial No. 373,193, filed January4, 1941.

The :,7 dihydroxy-fl,fl-dimethylbutyramide compounds of this inventionare of great utility as intermediates in the preparation of pantothenicacid compounds. The new amides may very conveniently be prepared fromc-hydroxyp,p-dimethyl- -butyrolactone by the action of ammonia. This maybe accomplished either by passing ammonia into a solution of the lactonein organic solvents, such as methanol or ethanol, or more conveniently,by reacting the lactone with liquid ammonia and then removing the excessammonia to obtain the amide.

The invention may be illustrated by the following specific example:

Racemic a-hydroxy-,ap-dimethyl-v-butyrolactone may be prepared forexample as described by Kohn and Neustadter, Monatsh. 39, 293 (1918).The lactone of melting point about 56 as thus obtained is suitable toruse without further purification.

75 grams of a-hydroxy-Bfl-dimethyl-'y-butyrolactone is dissolved inabout 400 cc. of liquid ammonia in an open vessel such as a. 2 l. flask.The lactone dissolves immediately in the liquid ammonia with formationof a clear solution.

After standing overnight, all of the ammonia has evaporated to leave acrystalline solid. This solid is triturated with petroleum ether,collected on a funnel and washed several times with petroleum ether. Thecrude product thus obtained is recrystallized from about ten times asmuch acetone. As thus obtained, the product, dl-adihydroxy-p,p-dimethylbutyramide, has a melting point of l26-127 C. Itis insoluble in petroleum ether and chloroform, somewhat soluble inacetone and quite soluble in alcohol. With aqueous sodium carbonatesolution no ammonia is evolved, but with boilingaqueous sodium hydroxidesolution ammonia is evolved. This shows that the substance is an amiderather than an ammonium salt. The yield is about 60 grams.

A sample was analyzed with the following results: Calc. for C49.0%;H-8.90%; N--9.52%; Found, C, 49.4%, 49.38%; H, 9.19%, 9.00%; N, 9.43%.9.51%.

Instead of using the racemic lactone as above to obtain the racemicamide, one may useeither oi. the optically active forms of the lactone,thereby obtaining the optically active forms of the amide. Thus, the()a-hydroxy-p,p-dimethylquinine salt in the resolution of thedl-lactone. yields the (+)-1, -dihydroxy-p,p-dimetliylbutyramide havinga. melting point of 94 C. and [a] =+52 (in 2% methanolic solution).Similarly, the -c-hydroxy-p,p-di methyl-'y-butyrolactone ([al=approximately +50 in 2% aqueous solution), obtained from the moresoluble quinine salt in the resolution of the dl-lactone, yields the-,'y-dihydroxy-pfl-dimethylbutyramide having a melting point of 94 C.and [cl of approximately 52. The optically active amides have, in eachcase, the same melting point, 94 C., and rotations of thesame magnitude,but opposite sign.

The new compounds of this invention may be reacted with the alkali metalsalts of p-alanine or with esters such as the methyl ester or ethylester of mil-alanine, thereby producing compounds oi' pantothenic acidas described and claimed in our application, Serial No. 373,193 abovereferred to.

What we claim as our invention is:

1. The process which comprises treatingczhydroxy-p,p-dimethyl-y-butyrolactone with ammonia to formen-dihydroXy-fifi-dimethylbutyramide.

2. The process which comprises reactinga-hydroxy-p,p-dimethyl-y-butyrolactone with liquid solution), obtainedfrom the more insoluble ammonia to form butyramide.

3. The process which comprises treating racemic a-hydroxy-p,p-dimethyl--butyrolactone with ammonia to form dl-,'-dihydroXy-flfi-dimethylbutyramide.

4. The process which comprises treating a hydroxyp,fl-dimethyl-v-butyrolactone with ammonia to form-dihydroxy-p,p-dimethylbutyramide.

5. The process which comprises treating a-hydroxy-fifi-dimethyl 1butyrolactone with ammonia to form()-a,-y-dihydroxy-p,p-dimethylbutyramide.

6. dl-a;y-Dihydroxy -p,,s dimethylbutyramide. having a melting point ofapproximately 126-127" C.

'l. -,-y-Dihydroxy-p,fl-dimethylbutyramide, having a melting point 01'approximately 94 C. and law of approximately +52 in 2% methanolicsolution.

8. -e -Dlhydroxy-Ap-dimethylbutyramide. having a melting point ofapproximately 94 C. and of approximately 52 in 2% methanolic solution.

an-dihydroxy-ap-dimethyl- HMER J. LAWSON. HERVEY C. PARKE. LEON A.SWEET.

DISCLAIMER 2,358,337.-El1mr J. Lawson, Newtonville, N. Y., and Hervey0'. Parke and Leon 'A. Sweet, Detroit, Mich. VITAMIN INTERMEDIATES ANDTHEIR PREPARATION. Patent dated Sept. 19, 1944. Disclaimer filed Oct.16, 1946, by the assignee, v Parke, Dam's c5: Company. Hereby entersthis disclaimer to claims 4 and 7.

[Oflicial Gazette November 26, 1946.]

